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首页> 外文期刊>Molecular and Cellular Biology >CREB-1α Is Recruited to and Mediates Upregulation of the Cytochrome c Promoter during Enhanced Mitochondrial Biogenesis Accompanying Skeletal Muscle Differentiation
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CREB-1α Is Recruited to and Mediates Upregulation of the Cytochrome c Promoter during Enhanced Mitochondrial Biogenesis Accompanying Skeletal Muscle Differentiation

机译：在增强的线粒体生物合成伴随骨骼肌分化过程中，CREB-1α被招募并介导细胞色素c启动子的上调。

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To further understand pathways coordinating the expression of nuclear genes encoding mitochondrial proteins, we studied mitochondrial biogenesis during differentiation of myoblasts to myotubes. This energy-demanding process was accompanied by a fivefold increase of ATP turnover, covered by an eightfold increase of mitochondrial activity. While no change in mitochondrial DNA copy number was observed, mRNAs as well as proteins for nucleus-encoded cytochrome c, cytochrome c oxidase subunit IV, and mitochondrial transcription factor A (TFAM) increased, together with total cellular RNA and protein levels. Detailed analysis of the cytochrome c promoter by luciferase reporter, binding affinity, and electrophoretic mobility shift assays as well as mutagenesis studies revealed a critical role for cyclic AMP responsive element binding protein 1 (CREB-1) for promoter activation. Expression of two CREB-1 isoforms was observed by using specific antibodies and quantitative reverse transcription-PCR, and a shift from phosphorylated CREB-1Δ in myoblasts to phosphorylated CREB-1α protein in myotubes was shown, while mRNA ratios remained unchanged. Chromatin immunoprecipitation assays confirmed preferential binding of CREB-1α in situ to the cytochrome c promoter in myotubes. Overexpression of constitutively active and dominant-negative forms supported the key role of CREB-1 in regulating the expression of genes encoding mitochondrial proteins during myogenesis and probably also in other situations of enhanced mitochondrial biogenesis.
机译：为了进一步了解协调编码线粒体蛋白的核基因表达的途径，我们研究了成肌细胞分化为肌管的过程中线粒体的生物发生。此能量需求过程伴随着ATP转换增加了五倍，而线粒体活性增加了八倍。虽然未观察到线粒体DNA拷贝数的变化，但核编码的细胞色素 c ，细胞色素 c 氧化酶亚基IV和线粒体转录因子A（TFAM）的mRNA和蛋白质），以及总细胞RNA和蛋白质水平的增加。通过荧光素酶报道分子，结合亲和力和电泳迁移率变动分析以及诱变研究对细胞色素 c 启动子进行了详细分析，揭示了环状AMP响应元件结合蛋白1（CREB-1）对于启动子的关键作用激活。通过使用特异性抗体和定量逆转录-PCR观察到了两种CREB-1亚型的表达，并且显示了从成肌细胞中的磷酸化CREB-1Δ到肌管中的磷酸化CREB-1α蛋白的转变，而mRNA的比率保持不变。染色质免疫沉淀实验证实，CREB-1α原位优先结合于肌管中的细胞色素 c 启动子。组成性活性和显性负性形式的过度表达支持CREB-1在肌生成过程中以及在其他增强线粒体生物发生的情况下，调节编码线粒体蛋白的基因表达的关键作用。

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